Diimidazo[4,5-b:4′,5′-e]pyridine: synthesis and nucleophilic aromatic substitution reaction

Article abstract of DOI:10.1016/j.mencom.2019.03.022

1,7-Dihydrodiimidazo[4,5-b:4′,5′-e]pyridine obtained by reductive heterocyclization was N-arylated with 4-fluoronitrobenzene to form two regioisomers in 7: 3 ratio. This N-arylation is considered as a model reaction for the polymer synthesis.

Full text of DOI:10.1016/j.mencom.2019.03.022

Mendeleev
Communications
Mendeleev Commun., 2019, 29, 181–183
Diimidazo[4,5-b:4',5'-e]pyridine: synthesis
and nucleophilic aromatic substitution reaction
Dmitriy Yu. Razorenov,* Sophia A. Makulova, Ivan V. Fedyanin, Konstantin A. Lyssenko,
Kirill M. Skupov, Yulia A. Volkova, Ivan I. Ponomarev and Igor I. Ponomarev
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. E-mail: razar@ineos.ac.ru
DOI: 10.1016/j.mencom.2019.03.022
O2N
H2N
NO2
N
N
N
N
H2, Pd/C
HCOOH
1,7-Dihydrodiimidazo[4,5-b:4',5'-e]pyridine obtained by
reductive heterocyclization was N-arylated with 4-fluoro-
nitrobenzene to form two regioisomers in 7:3 ratio. This
N-arylation is considered as a model reaction for the polymer
synthesis.
HN
NH
Ar
N
N
NH2
N
N
N
N
N
ArF
+
K2CO3,
DMA
N
N
N
Ar
Ar = 4-O2NC6H4
Ar
(7 : 3)
Ar
Heterocyclic polymers are useful as high-performance materials
including proton-conductive membranes for fuel cells. In these
membranes, heterocyclic polymers, usually containing benz-
imidazole or pyridine moieties, are doped with H3PO4 that
provides proton conductivity at higher temperatures (120–200°C)1
compared to those for Nafion-type or other membranes with
different acidic groups.2,3 The majority of known syntheses of
such heterocyclic polymers involve hazardous substances such
as tetraamines, require corrosive solvents like polyphosphoric acid
and Eaton’s reagent, and produce significant amounts of acidic
waste. Therefore, the search for cleaner procedures towards such
polymers is still actual.4 Previously, we prepared poly(N-phenylene-
benzimidazoles) by nucleophilic aromatic substitution5 and bis(benz-
imidazole) monomers from bis(o-nitroanilines)6 depriving tetra-
amine intermediates. In the following work we considered the
similar pathway for 1,7-dihydrodiimidazo[4,5-b:4',5'-e]pyridine
(DIP) – a potential monomer for M5-like fibers.7 This compound
contains five nitrogen atoms, so we supposed that in a polymer
chain they would effectively bind with H3PO4 to form a polymer-
electrolyte complex required for proton-conductive membranes.
Despite of the simple-looking formula of DIP, its synthesis
has been documented scarcely.8–10 Bredereck8 reported on 7% yield
as a result of cyclization between aminoacetonitrile and form-
amidine, with the product having been characterized with elemental
analysis and paper chromatography only. Wang9 performed cyclo-
condensation of 2,3,5,6-teraaminopyridine with formaldehyde
with further air oxidation providing 74% yield of DIP. This
substance was characterized by NMR spectrum, which was later
proved to closely agree with that for the product obtained by
us. Guozheng and Ming10 reported the synthesis of DIP from
2,3,5,6-tetraaminopyridine and triethyl orthoformate, however,
their NMR data were completely different and controversial.
Our reductive heterocyclization procedure was inspired by the
work of Hanan,11 in which various aromatic and heteroaromatic
o-nitro amines were converted to benzimidazoles in formic acid/
PriOH media with iron powder and NH4Cl within 1–2 h. To
synthesize bis(benzimidazole) from bis(o-nitroanilines), we had
to modify this method, using Pd/C catalyst and hydrogen bubbling
through the mixture at atmospheric pressure instead of iron metal
as a reducing agent, the solvent was changed to HCOOH/H2O
mixtures, and the reaction time had to be prolonged up to 20 h to
obtain products in high yields (95–99%).6
We supposed that a similar approach should work for DIP
synthesis. Commercial 2,6-diaminopyridine 1 was transformed
into hydrosulfate 2 and then nitrated with sodium nitrate in
oleum to obtain 2,6-diamino-3,5-dinitropyridine 3 (Scheme 1).†
Unfortunately, under the conditions suitable for the reductive
heterocyclization synthesis of bis(benzimidazole) in the case of
H
H2N
N
NH2
H2N
N
NH2
i
ii
· 0.5 SO42–
1
2
N
H2N
O2N
N
NH2
N
N
iii
vi
· 2 HCl
5 · H2O
HN
NH
5 · 2 HCl
NO2
H2N
H2N
3
N
NH2
iv
v
NH2
4 (· n HCl)
Scheme 1 Reagents and conditions: i, H2SO4, PriOH; ii, NaNO3, oleum;
iii, H2 (90 atm), Pd/C, HCOOH, MeOH, 100°C, 12 h, then HCl; iv, H2,
autoclave, Pd/C, then HCl; v, HCOOH, HCl, D; vi, NH3/H2O.
†
2,6-Diaminopyridine 1 (20 g, 0.18 mol) was dissolved in propan-2-ol
(180 ml), the solution was filtered, and concentrated sulfuric acid (8 g)
was slowly added. The mixture was cooled to room temperature, the
precipitated 2,6-diaminopyridine hydrosulfate was filtered and washed
with a small amount of ethanol and propan-2-ol, then dried in vacuo
to give 22.8 g (79%) of a yellowish powder. Oleum (40 ml) was poured
into a three-necked flask equipped with a magnetic stirrer and placed in
an ice bath. After cooling, 2,6-diaminopyridine hydrosulfate 2 (10.0 g,
6.3 mmol) was added portionwise with vigorous stirring. Sodium nitrate
(11.0 g, 7.7 mmol) was slowly added, then the mixture was poured onto
ice (1 kg), the orange-brown precipitate was filtered off, washed and dried
to give 9.2 g (80%) of compound 3. 1H NMR (400 MHz, DMSO-d6) d:
9.01 (s, 1H), 8.44 (s, 2H), 8.28 (s, 2H). Lit.,5 d: 9.00 (s, 1H), 8.43 (s,
2H), 8.27 (s, 2H).
© 2019 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
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Mendeleev Commun., 2019, 29, 181–183
H(3)
N(3)
H(7)
N(7)
C(8)
N(5)
HCl for 4 h, which is a common procedure for benzimidazole
synthesis,12 to get identical DIP·2HCl in 30% yield. Salt DIP·2HCl
was converted into hydrate form (DIP·H2O) by heating in aqueous
ammonia. Both hydrate and hydrochloride forms were tested in a
model reaction of nucleophilic aromatic substitution with 4-fluoro-
nitrobenzene (Scheme 2).¶
C(6)
C(4)
C(2)
N(1)
C(12)
C(10)
N(9)
H(9)
C(11)
H(1)
NO2
N
Figure 1 General view of the dication of DIP·2H+ (5·2HCl) in thermal
ellipsoid representation (p = 50%). Chloride anions are omitted for clarity.
N
N
K2CO3
DMA
+
HN
NH
F
NO2
5
6
compound 3 a complex mixture of hardly identified substances
was formed. The reaction was incomplete even after 3 days, so
we decided to carry out the process at higher pressure in an
autoclave. Under these conditions, the desired DIP 5 was obtained
in 31% yield‡ (see Scheme 1). For better purification, HCl was
used to recrystallize DIP in hydrochloride form, and the obtained
crystals were characterized by the X-ray data (Figure 1).§
The molecular structure of compound 5 is the first example of
the crystal containing the 1,7-dihydrodiimidazo[4,5-b:4',5'-e]-
pyridine heterocyclic system. Due to dicationic character, the
bond lengths C–N with atoms C(2) and C(8) in five-membered
rings of the hererocycles are almost equalized, as well as C–N
bonds with exocyclic to pyridine ring. The four H atoms attached
to nitrogen atoms participate in N–H···Cl hydrogen bonds of the
moderate strength [N···Cl 3.056(4)–3.102(4) Å], connecting the
ions into zigzag-like layers.
N
N
N
N
N
N
N
N
+
N
N
O2N
NO2 O2N
(7 : 3)
7a
7b
Scheme 2
The conditions of the model reaction were chosen to be close
to the polymer synthesis with bis(benzimidazole) monomers.4,5
According to our previous experience, sonification of the monomer
with K2CO3 at the beginning of the synthesis increases the
reaction rate and helps to obtain polymers with higher molecular
weights. The role of K2CO3 here is to deprotonate NH from the
imidazole cycle, and so, additional quantity of K2CO3 is required
to scavenge HCl from salt DIP·2HCl. Theoretically, DIP has five
tautomeric forms, so one may suppose that this could affect
the reaction outcome.Yet, the deprotonation of these forms leads
to a single anion structure. The nitrogen atom in the central
Alternatively, DIP 5 was synthesized via tetraamine pathway
(see Scheme 1). 2,3,5,6-Teraaminopyridine 4 hydrochloride was
prepared by a known method in autoclave,5 that required large
amounts of HCl and THF for its sedimentation. The obtained
tetraamine 4 was refluxed in a mixture of formic acid and 18%
‡
2,6-Diamino-3,5-dinitropyridine 3 (10 g, 5 mmol), Pd/C (0.7 g, 5%),
formic acid (225 ml, 90%) and methanol (75 ml) were placed in a 500 ml
autoclave, the vessel was filled with hydrogen (90 atm). The autoclave
was heated at 100°C for 12 h, then cooled to room temperature to reveal
that 15 atm of H2 were consumed. The mixture was concentrated with
rotary evaporator at 80°C (140 mbar), dissolved in hot concentrated HCl
(200 ml) and filtered from the catalyst. The precipitate obtained after
cooling was filtered and once again recrystallized from HCl with addition
of activated charcoal to obtain 3.67 (31%) of pure DIP·2HCl as yellowish
crystals. 1H NMR (400 MHz, D2O) d: 9.07 (s, 2H), 8.32 (s, 1H). 1H NMR
(400 MHz, DMSO-d6, NEt3) d: 8.39 (s, 2H), 8.18 (s, 1H). Found (%):
Cl, 30.43. Calc. for C7H5N5·2HCl (%): Cl, 30.55.
¶
Salt DIP·2HCl (0.464 g, 2 mmol), K2CO3 (0.691 g, 5 mmol), N,N-di-
methylacetamide (DMA, 5 ml) and toluene (2 ml) were placed in a
two-necked flask with a mechanical stirrer and argon inlet and sonicated
at 80°C for 20 min in ultrasonic bath. Then 4-fluoronitrobenzene (0.564 g,
4 mmol) was added, and the flask was placed into a silicon bath and
heated up to 110°C. Soon the mixture acquired a rich violet color, which
then faded into light yellow. After 20 h of heating the mixture was poured
into water, the precipitate was filtered off, washed and dried in vacuo to
give 0.73 g (87%) of the product.
Similar procedure was performed for DIP·H2O (0.354 g, 2 mmol) with
a reduced quantity of K2CO3 (0.414 g, 3 mmol) and an additional 1 h
heating of the reaction mixture at 110°C to remove the hydrate water
before the addition of 4-fluoronitrobenzene, 0.836 g (99%) of the product
were obtained.
Salt DIP·2HCl (1 g, 4.7 mmol) was heated in 20 ml of 10% aq. NH3,
filtered and dried at 50°C in vacuo to obtain white powder of neutralized
form DIP·H2O in quantitative yield (0.76 g). 1H NMR (400 MHz,
DMSO-d6) d: 12.87 (s, 2H), 8.40 (s, 2H), 8.19 (s, 1H). 13C NMR
(101 MHz, DMSO-d6) d: 148.51, 143.94, 128.60, 111.21. Found (%):
C, 47.73; H, 3.83; N, 39.51. Calc. for C7H5N5·H2O (%): C, 47.46; H, 3.98;
N, 39.53. Lit.,9 1H NMR (500 MHz, DMSO-d6) d: 12.77–12.72 (s, 2H),
8.38 (s, 2H), 8.18–8.14 (s, 1H).
The reaction product (100 mg) was dissolved in DMA (6 ml), centri-
fuged for 1 h at 3000 rpm, the supernatant was separated from the residue
of ‘trans’ (7b) product (19 mg) and precipitated with water to give 60 mg
of ‘cis-1’ (7a) product. NMR spectra of the products are presented and
discussed in Online Supplementary Materials.
§
Crystal data for 5: monoclinic, space group P21, a = 4.7530(6), b =
= 10.9303(14) and c = 8.6048(11) Å, b = 95.439(3)°, V = 445.02(10) Å3,
Z = 2 (Z' = 1), dcalc = 1.732 g cm–3, R1 = 0.0342 [for 2301 reflections with
I > 2s(I)], wR2 = 0.0819, GOF = 1.030.
Crystal data for 7a: monoclinic, space group C2/c, a = 22.399(3), b =
= 14.2557(16) and c = 7.1186(8) Å, b = 99.297(2)°, V = 2243.2(4) Å3,
Z = 4 (Z' = 0.5), dcalc = 1.461 g cm–3 (without SQUEEZed solvent), R1 =
= 0.0424 [for 2547 reflections with I > 2s(I)], wR2 = 0.1190, GOF = 1.054.
Crystal data for 7b: monoclinic, space group P21/n, a = 10.0092(3),
b = 13.7495(4) and c = 15.3130(5) Å, b = 94.4884(16)°, V = 2100.93(11) Å3,
Z = 2 (Z' = 0.5), dcalc = 1.716 g cm–3, R1 = 0.0532 [for 5034 reflections
with I > 2s(I)], wR2 = 0.1371, GOF = 1.007.
The diffraction experiment for 5 was performed on a Bruker Smart
Apex II, and for 7a,b on a Bruker Apex DUO diffractometer; for all
samples at 120 K using MoKa radiation (l = 0.71072 Å).
CCDC 1868389–1868391 contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk.
Major product, 1,7-bis(4-nitrophenyl)-1,7-dihydrodiimidazo[4,5-b:4',5'-e]
pyridine 7a: mp 370–380°C. H NMR (400 MHz, DMSO-d6) d: 9.09
-
1
(s, 2H), 8.52 (s, 1H), 8.47 (d, 4H, J 8.9 Hz), 8.15 (d, 4H, J 8.9 Hz).
13C NMR (101 MHz, DMSO-d6) d: 154.34, 146.95, 146.46, 141.48, 126.09,
124.53, 123.31, 103.31. Found (%): C, 55.99; H, 3.01; N, 23.88. Calc. for
C19H11N7O4·H2O (%): C, 54.42; H, 3.12; N, 23.38.
Minor product, 1,5-bis(4-nitrophenyl)-1,5-dihydrodiimidazo[4,5-b:5',4'-e]-
pyridine 7b: mp > 400°C. 1H NMR (400 MHz, CF3COOD) d: 10.44
(s, 1H), 10.37 (s, 1H), 9.51 (s, 1H), 9.07 (d, 2H, J 8.7 Hz), 9.03 (d, 2H,
J 8.4 Hz), 8.59 (d, 2H, J 8.7 Hz), 8.46 (d, 2H, J 8.4 Hz). 13C NMR
(101 MHz, CF3COOD) d: 153.13, 152.52, 148.95, 148.66, 146.52, 146.39,
140.48, 139.98, 130.02, 129.85, 129.45, 129.29, 128.37, 127.88. Found (%):
C, 54.44; H, 3.24; N, 23.03. Calc. for C19H11N7O4·H2O (%): C, 54.42;
H, 3.12; N, 23.38.
– 182 –

Mendeleev Commun., 2019, 29, 181–183
O(2)
O(2A)
The crystal structure of ‘trans’ isomer 7b (Figure 3)§ corre-
O(1)
O(1A)
N(14)
N(14A)
sponds to hydrotrifluoroacetate which also contains four neutral
solvate trifluoroacetic acid molecules. It is pseudo-centrosym-
metric, with the exception of N(5) and C(6) atoms of the pyridine
ring. In the centrosymmetric crystal structure 7b (space group
P21/c), the substituted dication lies on the inversion center in
two different orientations, with almost overlapping positions
of N(5) and C(6) atoms. Like in dication 5, the lengths of
N(1)–C(2) and C(2)–N(3) bonds of the five-membered rings
are closer to values between double and single bonds.§
In summary, DIP can be readily subjected to aromatic nucleo-
philic substitution reaction resulting in C–N coupling with both
imidazole rings, so it can be considered a promising monomer for
the polymer synthesis. Its synthesis from 1,5-diamino-2,4-dinitro-
pyridine has yet to be optimized to achieve higher yields.
C(11A)
C(11)
C(10)
C(12)
C(13)
C(12A)
C(13A)
C(10A)
C(9A)
C(9)
C(8A)
C(8)
C(6)
C(7A)
C(7)
C(4)
N(1)
N(1A)
C(2A)
C(2)
C(4A)
N(3)
N(3A)
N(5)
Figure 2 General view of the molecule of 7a in thermal ellipsoid repre-
sentation (p = 50%). Solvate formic acid molecules are omitted for clarity.
six-membered ring seems less likely to be involved into C–N
coupling, so three potential products can be expected for this
reaction: two ‘cis’ and one ‘trans’. The analysis of the reaction
products by NMR showed mainly the presence of two isomers:
‘cis-1’ (7a) and ‘trans’ (7b) in 7:3 ratio, which was almost
unaffected by the form of DIP used. The solubility of these
substances in organic solvents appeared to be different, so they
were separated by centrifugation and analyzed individually.
The crystals of the isolated isomers, required for the X-ray
study, were prepared in formic and trifluoroacetic acid for ‘cis’
and ‘trans’ products, respectively. In contrast to structure 5, the
crystal 7a (Figure 2)§ contains the substituted heterocyclic
molecule in neutral form, as well as neutral formic acid molecule
and heavily disordered unidentified solvate in channel-like voids.
The strength of the formic acid is therefore insufficient to protonate
the heterocycle. The heterocyclic molecule lies on crystallo-
graphic axis 2, only the half of it being symmetry independent.
In contrast to dication 5, the lengths of the N(1)–C(2) and
C(2)–N(3) bonds indicate their single and double character in
full accordance with a canonical structure. The solvate formic
acid molecules disordered by two positions participate in H-bonds
with nitrogen atom N(3).
This work was supported by the Russian Science Foundation
(grant no. 18-13-00421). The contribution of Center for Molecular
Composition Studies of INEOS RAS is gratefully acknowledged.
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi: 10.1016/j.mencom.2019.03.022.
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Received: 4th October 2018; Com. 18/5711
– 183 –